Aerosol formulation for copd

ABSTRACT

Stable aerosol solution formulations comprising glycopyrronium bromide are useful for administration to patients with COPD and other respiratory conditions.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.09015980.7 filed on Dec. 23, 2009, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical aerosol solutionformulations comprising glycopyrronium bromide, intended for use inpressurized metered dose inhalers. The present invention further relatesto use of such formulations in the prevention and therapy of respiratorydisorders, including chronic obstructive pulmonary disease (COPD).

2. Discussion of the Background

Glycopyrronium bromide (also known as glycopyrrolate) is a muscarinic M3anticholinergic agent used to reduce salivation associated withadministration of certain anaesthetics, and as adjunctive therapy forpeptic ulcers. It has also been reported to be effective in thetreatment of asthmatic symptoms (Hansel et al., Chest, 2005;128:1974-1979).

WO 2005/107873 disclose the use of glycopyrrolate for the treatment ofchildhood asthma.

WO 01/76575 discloses a controlled release formulation for pulmonarydelivery of glycopyrrolate. The formulation is intended for use intreatment of respiratory disease, in particular chronic obstructivepulmonary disease (COPD). The application focuses on dry powderformulations suitable for delivery by means of a dry powder inhaler(DPI).

One of the drawbacks of DPIs is that insufficient patient inhalationflow rates may lead to reduced dose delivery and incompletedeaggregation of the powder, leading to unsatisfactory deviceperformance. For this reason DPIs are normally used only in olderchildren and adults. Younger children and other people with inhalationdifficulties can benefit from use of propellant-based aerosolformulations, administered by pressurized metered dose inhalers (pMDIs).pMDIs use propellant to expel droplets containing the pharmaceuticalproduct to the respiratory tract in an aerosol.

It would be desirable to provide a clinically useful aerosol product inthe form of a solution that delivers the therapeutic benefits ofglycopyrronium bromide in effective and consistent doses over anextended product lifetime, and ideally without the need for storageunder special conditions of temperature or humidity.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelpharmaceutical aerosol solution formulations comprising glycopyrroniumbromide, intended for use in pressurized metered dose inhalers.

It is another object of the present invention to provide novel methodsfor the prevention and therapy of respiratory disorders, including COPD.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat pharmaceutical compositions comprising glycopyrronium bromidedissolved in an HFA propellant, an optional co-solvent, and an amount ofacid sufficient to stabilize the glycopyrronium bromide are useful forthe prevention and therapy of respiratory disorders, including COPD.

Additional pharmaceutically active ingredients may also be included.

In a further aspect, the present invention provides a pressurizedmetered dose inhaler or other container suitable for aerosol delivery,comprising the pharmaceutical composition of the invention.

In another aspect, the present invention provides the use ofpharmaceutical compositions as described herein for the therapeutic orpalliative treatment or prevention of respiratory disease conditions,such as COPD.

In another aspect, the present invention provides methods for thetherapeutic or palliative treatment or prevention of respiratory diseaseconditions, such as COPD.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A solution formulation of glycopyrronium bromide in HFA propellant withethanol as co-solvent was prepared and checked for stability after 3months following storage under different conditions of temperature andhumidity. One batch was stored under optimal conditions (refrigeration);the other batches were stored under accelerated degradation conditionsof high temperature and humidity. Although the refrigerated batchremained stable over the 3 month period, the other batches degradedsignificantly over that time-span. This is the first time thatglycopyrronium bromide has been observed to exhibit poor stability inany type of formulation.

Thus, a simple aerosol solution formulation of glycopyrronium bromidedissolved in propellant and co-solvent fails to meet the requirementsfor practical use, namely that it should be capable of being carried onthe person without refrigeration and yet deliver consistent dosages ofactive ingredient.

The present inventors were able to overcome these stability issues byinclusion of a specific amount of inorganic acid in the formulation. Inparticular, they found that inclusion of an amount of 1M hydrochloricacid (HCl) in the range of 0.005 to 1.0 μg/μl, preferably 0.099-0.74μg/μl, and more preferably 0.18-0.32 μg/μl, to the solution issufficient to eliminate degradation of glycopyrronium bromide over anextended period of non-optimal storage, thereby ensuring a consistentdose of glycopyrronium bromide per actuation of the pMDI containing thesolution formulation.

Glycopyrronium bromide, chemically defined as3-[(cyclopentylhydroxy-phenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide, has two chiral centers corresponding to four potentialdifferent stereoisomers with configurations (3R,2′R), (3S,2′R),(3R,2′S), and (3S,2′S). Glycopyrronium bromide in the form of any ofthese pure enantiomers or diastereomers or any combination thereof maybe used in practising the present invention. In one embodiment of thepresent invention, the(3S,2′R),(3R,2′S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide racemic mixture, also known as glycopyrrolate is preferred.Glycopyrronium bromide is present in the formulation in an amount in therange from 0.005 to 0.14% (w/w), preferably from 0.010 to 0.13% (w/w),more preferably from 0.015 to 0.04% (w/w), wherein % (w/w) means theamount by weight of the component, expressed as percent with respect tothe total weight of the composition.

Glycopyrrolate is commercially available, and can be synthesizedaccording to the process described in U.S. Pat. No. 2,956,062 or inFranko B V and Lunsford C D, J. Med. Pharm. Chem., 2(5), 523-540, 1960.

The propellant component of the composition may be anypressure-liquefied propellant and is preferably a hydrofluoroalkane(HFA) or a mixture of different HFAs, more preferably selected from thegroup consisting of HFA134a (1,1,1,2-tetrafluoroethane), HFA 227(1,1,1,2,3,3,3-heptafluoropropane, and mixtures thereof. The preferredHFA is HFA134a. HFAs may be present in the formulation in an amount inthe range from 75 to 95% (w/w), preferably from 85 to 90% (w/w), wherein% (w/w) means the amount by weight of the component, expressed aspercent with respect to the total weight of the composition.

The co-solvent incorporated into formulation of the present inventionhas a higher polarity than that of the propellant and may include one ormore substances such as a pharmaceutically acceptable alcohol, inparticular ethanol, or a polyol such as propylene glycol or polyethyleneglycol.

Advantageously the co-solvent is selected from the group of lowerbranched or linear alkyl (C₁-C₄) alcohols such as ethanol and isopropylalcohol. Preferably the co-solvent is ethanol.

The concentration of the co-solvent will vary depending on the finalconcentration of the active ingredient in the formulation and on thetype of propellant. For example ethanol may be used in a concentrationcomprised in the range from 5 to 25% (w/w), preferably from 8 to 20%(w/w), more preferably from 10 to 15% (w/w), wherein % (w/w) means theamount by weight of the component, expressed as percent with respect tothe total weight of the composition. In one of the preferredembodiments, the concentration of ethanol is 12% (w/w).

The ratio of propellant to co-solvent in the formulation is preferablyin the range 50:50 to 95:5 (w/w).

It is envisaged that HCl of a different molarity or alternativeinorganic acids (mineral acids) could substitute for 1M HCl in theformulations of the invention. For instance, alternative acids could beany pharmaceutically acceptable monoprotic or polyprotic acid, such as(but not limited to): hydrogen halides (hydrochloric acid hydrobromicacid, hydroiodic acid etc.) phosphoric acid, nitric acid, sulphuricacid, and halogen oxoacids.

The pharmaceutically active components of the composition are preferablecompletely and homogeneously dissolved in the mixture of propellant andco-solvent, i.e. the composition is preferably a solution formulation.

Optionally, the solution formulation compositions may comprise otherpharmaceutical excipients or additives known in the art. In particular,the compositions of the present invention may comprise one or more lowvolatility components. Low volatility components are useful in order toincrease the mass median aerodynamic diameter (MMAD) of the aerosolparticles upon actuation of the inhaler and/or to improve the solubilityof the active ingredient in the propellant/co-solvent mixture.

The low volatility component, when present, has a vapor pressure at 25°C. lower than 0.1 kPa, preferably lower than 0.05 kPa. Examples oflow-volatility components may be esters such as isopropyl myristate,ascorbyl myristate, tocopherol esters; glycols such as propylene glycol,polyethylene glycol, glycerol; or surface active agents such as asaturated organic carboxylic acid (i.e. lauric, myristic, stearic acid)or an unsaturated carboxylic acid (i.e. oleic or ascorbic acid).

The amount of low volatility component may vary from 0.1 to 10% w/w,preferably from 0.5 to 5% (w/w), more preferably between 1 and 2% (w/w),wherein % (w/w) means the amount by weight of the component, expressedas percent with respect to the total weight of the composition.

In one embodiment of the present invention, an amount of water comprisedbetween 0.005 and 0.5% (w/w), wherein % (w/w) means the amount by weightof the component, expressed as percent with respect to the total weightof the composition, may optionally be added to the formulations in orderto favourably affect the solubility of the active ingredient withoutincreasing the MMAD of the aerosol droplets upon actuation.

Advantageously, the formulations of the present invention are free ofexcipients (such as surfactants) other than the co-solvent, thepropellant, and a stabilizing amount of an acid.

The present invention also relates to a method for preparing apharmaceutical composition, comprising adding 1M HCl to a solution ofglycopyrronium bromide in HFA propellant and co-solvent, wherein theamount of 1M HCl added is in the range of 0.005 to 1.0 μg per μl of thefinal solution.

The pharmaceutical compositions of the present invention may furthercomprise other, additional pharmaceutically active agents for separate,sequential or simultaneous use. Optional additional pharmaceuticallyactive components of the composition include any known in the art forprophylaxis or treatment of respiratory diseases and their symptoms.Examples of these active components are: beta-2-agonists such asformoterol, salbutamol, fenoterol, carmoterol (TA 2005), indacaterol,milveterol, vilanterol (GSK 642444), terbultaline, salmeterol,bitolterol, metaproterenol all in form of single stereoisomers ormixtures thereof and salts thereof; corticosteroids such asbeclometasone dipropionate, fluticasone propionate, butixocort,mometasone furoate, triamcinolone acetonide, budesonide and its22R-epimer, ciclesonide, flunisolide, loteprednol, and rofleponide;other anti-muscarinic drugs such as methscopolamine, ipratropiumbromide, oxitropium bromide and tiotropium bromide; phosphodiesterase IVinhibitors such as: cilomilast, roflumilast and tetomilast. Among theseadditional active components formoterol fumarate is particularlypreferred.

The compositions of the present invention can be inhaled from anysuitable MDI device known to the skilled person. Desired doses of theindividual pharmaceutically active components of the formulation aredependent on the identity of the component and the type and severity ofthe disease condition, but are preferably such that a therapeutic amountof the active ingredient is delivered in one or two actuations.Generally speaking, doses of active ingredient are in the range of about0.5 μg to 1000 μg per actuation, e.g. about 1 to 100 μg/actuation, andsometimes about 5 to 50 μg/actuation. The skilled person in the field isfamiliar with how to determine the appropriate dosage for eachindividual pharmaceutically active ingredient.

With specific reference to glycopyrronium bromide, the preferred dosageis about 0.5 to 100 μg per actuation, preferably about 1 to 40 μg peractuation, more preferably about 5 to 26 μg per actuation, even morepreferably 25 μg per actuation.

The pharmaceutical formulation of the present invention is filled intopMDI devices known in the art. Said devices comprise a canister fittedwith a metering valve. Actuation of the metering valve allows a smallportion of the spray product to be released. Part or all of the canistermay be made of a metal, for example aluminium, aluminium alloy,stainless steel or anodized aluminium. Alternatively the canister may bea plastic can or a plastic-coated glass bottle.

The metal canisters may have part or all of the internal surfaces linedwith an inert organic coating. Examples of preferred coatings areepoxy-phenol resins, perfluorinated polymers such asperfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes suchas poly-tetrafluoroethylene (Teflon), fluorinated-ethylene-propylene(FEP), polyether sulfone (PES) or fluorinated-ethylene-propylenepolyether sulfone (FEP-PES) mixtures or combination thereof. Othersuitable coatings could be polyamide, polyimide, polyamideimide,polyphenylene sulfide or their combinations.

In certain embodiments, canisters having the internal surface lined withFEP-PES or Teflon may preferably be used.

In other particular embodiments, canisters made of stainless steel maybe used.

The container is closed with a metering valve for delivering a dailytherapeutically effective dose of the active ingredient. Generally, themetering valve assembly comprises a ferrule having an aperture formedtherein, a body moulding attached to the ferrule which houses themetering chamber, a stem consisting of a core and a core extension, aninner- and an outer-seal around the metering chamber, a spring aroundthe core, and a gasket to prevent leakage of propellant through thevalve.

The gasket seal and the seals around the metering valve may compriseelastomeric material such as EPDM, chlorobutyl rubber, bromobutylrubber, butyl rubber, or neoprene. EPDM rubbers are particularlypreferred. The metering chamber, core and core extension aremanufactured using suitable materials such as stainless steel,polyesters (e.g. polybutyleneterephthalate (PBT)), or acetals. Thespring is manufactured in stainless steel eventually including titanium.The ferrule may be made of a metal, for example aluminum, aluminumalloy, stainless steel or anodized aluminum. Suitable valves areavailable from manufacturers such as Valois, Bespak plc and3M-Neotechnic Ltd.

The pMDI is actuated by a metering valve capable of delivering a volumeof between 25 to 100 μl, preferably between 40 to 70 μl, and optionallyabout 50 μl, or about 63 μl per actuation.

Each filled canister is conveniently fitted into a suitable channelingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs of a patient. Suitable channeling devicescomprise, for example, a valve actuator and a cylindrical or cone-likepassage through which medicament may be delivered from the filledcanister via the metering valve to the mouth of a patient e.g. amouthpiece actuator.

In a typical arrangement, the valve stem is seated in a nozzle blockwhich has an orifice leading to an expansion chamber. The expansionchamber has an exit orifice which extends into the mouthpiece. Actuator(exit) orifices having a diameter in the range 0.15 to 0.45 mm and alength from 0.30 to 1.7 mm are generally suitable. Preferably an orificehaving a diameter from 0.2 to 0.44 mm is used, e.g. 0.22, 0.25, 0.30,0.33 or 0.42 mm.

In certain embodiments of the present invention, it may be useful toutilize actuator orifices having a diameter ranging from 0.10 to 0.22mm, in particular from 0.12 to 0.18 mm, such as those described in WO03/053501. The use of said fine orifices may also increase the durationof the cloud generation and hence, may facilitate the coordination ofthe cloud generation with the slow inspiration of the patient.

In case the ingress of water into the formulation is to be avoided, itmay be desired to overwrap the MDI product in a flexible package capableof resisting water ingress. It may also be desirable to incorporate amaterial within the packaging which is able to adsorb any propellant andco-solvent which may leak from the canister (e.g. a molecular sieve).

Optionally, the MDI device filled with the formulation of the presentinvention may be utilized together with suitable auxiliary devicesfavoring the correct use of the inhaler. Said auxiliary devices arecommercially available and, depending on their shape and size, are knownas “spacers”, “reservoirs” or “expansion chambers”. Volumatic™ is, forinstance, one of the most widely known and used reservoirs, whileAerochamber™ is one of the most widely used and known spacers. Asuitable expansion chamber is reported for example in WO 01/49350.

The formulation of the present invention may also be used with commonpressurized breath-activated inhalers such as those known with theregistered names of Easi-Breathe™ and Autohaler™.

The efficacy of an MDI device is a function of the dose deposited at theappropriate site in the lungs. Deposition is affected by the aerodynamicparticle size distribution of the formulation which may be characterizedin vitro through several parameters.

The aerodynamic particle size distribution of the formulation of theinvention may be characterized using a Cascade Impactor according to theprocedure described in the European Pharmacopoeia 6^(th) edition, 2009(6.5), part 2.09.18. An Apparatus E, operating at a flow rate range of30 litres/minute to 100 litres/minute or an Apparatus D-Andersen CascadeImpactor (ACI)-, operating at a flow rate of 28.3 l/minute, may beutilized. Deposition of the drug on each ACI plate is determined by highperformance liquid chromatography (HPLC).

The following parameters of the particles emitted by a pressurized MDImay be determined:

-   -   i) mass median aerodynamic diameter (MMAD) is the diameter        around which the mass aerodynamic diameters of the emitted        particles are distributed equally;    -   ii) delivered dose is calculated from the cumulative deposition        in the ACI, divided by the number of actuations per experiment;    -   iii) respirable dose (fine particle dose=FPD) is obtained from        the deposition from Stages 3 (S3) to filter (AF) of the ACI,        corresponding to particles of diameter ≦4.7 microns, divided by        the number of actuations per experiment;    -   iv) respirable fraction (fine particle fraction=FPF) which is        the percent ratio between the respirable dose and the delivered        dose; and    -   v) “superfine” dose is obtained from the deposition from Stages        6 (S6) to filter, corresponding to particles of diameter ≦1.1        microns, divided by the number of actuations per experiment.

The solutions of the present invention are capable of providing, uponactuation of the pMDI device in which they are contained, a total FPFhigher than 40%, preferably higher than 50%, more preferably higher than60%.

Moreover, the formulations of the present invention are capable ofproviding, on actuation, a fraction higher than or equal to 30% ofemitted particles of diameter equal to or less than 1.1 microns asdefined by the content stages S6-AF of an Andersen Cascade Impactor,relative to the total fine particle dose collected in the stages S3-AFof the impactor. Preferably the fraction of emitted particles ofdiameter equal to or less than 1.1 microns is higher than or equal to40%, more preferably higher than 50%, even more preferably higher than60%, most preferably higher than 70%.

According to a further aspect of the present invention there is provideda method of filling an aerosol inhaler with a composition of the presentinvention. Conventional bulk manufacturing methods and machinery wellknown to those skilled in the art of pharmaceutical aerosol manufacturemay be employed for the preparation of large-scale batches for thecommercial production of filled canisters.

The method comprises:

-   -   a) preparing a solution comprising glycopyrronium bromide, a        co-solvent (e.g. ethanol), a mineral acid, a propellant        comprising a HFA and optionally a low volatility component at a        temperature from −50 to −60° C. at which the solution does not        vaporize;    -   b) cold filling the inhaler with the prepared solution; and    -   c) placing the valve onto the can and crimping.

An alternative method comprises:

-   -   a) preparing a solution comprising glycopyrronium bromide, a        co-solvent (e.g. ethanol), a mineral acid, and optionally a low        volatility component;    -   b) filling the open can with the bulk solution;    -   c) placing the valve onto the can and (vacuum) crimping; and    -   d) pressure-filling the can with HFA propellant through the        valve.

A further alternative method comprises:

-   -   a) preparing a solution comprising glycopyrronium bromide, a        co-solvent (e.g. ethanol), a mineral acid, an optional low        volatility component and HFA propellant using a pressurised        vessel:    -   b) placing the valve onto the empty can and crimping; and    -   c) pressure-filling the can with the final solution formulation        through the valve.

The packaged formulations of the present invention are stable forextended periods of time when stored under normal conditions oftemperature and humidity. In a preferred embodiment, the packagedformulations are stable for at least 6 months at 25° C. and 60% RH, morepreferably for at least 1 year, most preferably for at least 2 years.Stability is assessed by measuring content of residual activeingredient. A “stable” formulation as defined herein means one retainingat least about 85%, preferably at least about 90%, and most preferablyat least about 95% of residual content of each active ingredient at agiven time point, as measured by HPLC-UV VIS.

The optimized stable formulations meet the specifications required bythe ICH Guideline Q1B or CPMP/QWP/122/02 Rev.1 relevant for drug productstability testing for the purposes of drug registration.

The product of the present invention may be used for prophylacticpurposes or for symptomatic relief of a wide range of respiratorydisorders, such as asthma of all types and chronic obstructive pulmonarydisease (COPD).

Other respiratory disorders for which use of the pharmaceuticalcompositions of the present invention may be beneficial are thosecharacterized by obstruction of the peripheral airways as a result ofinflammation and presence of mucus, such as chronic obstructivebronchiolitis, chronic bronchitis, emphysema, acute lung injury (ALI),cystic fibrosis, rhinitis, and adult or acute respiratory distresssyndrome (ARDS).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Glycopyrronium Bromide Stability During Storage withor without Acid Addition

Solution formulations were prepared with the compositions shown in Table1.

TABLE 1 Composition of the tested Gly pMDI solution formulations.Theoretical Unit Formula (μg/actuation for a 63 μl valve) GlycopyrroniumAnhydrous bromide (GLY) ethanol 1M HCl HFA 134a Total Without 25 8856 —64919 73800 Acid With 25 8856 14 64905 73800 Acid

The samples containing acid were formulated by the addition of 1M HCl inan amount corresponding to 0.222 μg/μl of the solution. The solution wasfilled into canisters which were stored inverted under differentconditions: 5°; 25° C./60% RH; 30° C./75% RH; 40° C./75% RH. The sampleswere analyzed chromatographically for glycopyrronium bromide contentafter 1 to 3 months of storage and after 6 months storage only for 5°;25° C./60% RH. The results are reported in the following Table 2.

TABLE 2 GLY pMDI can content (mean % residue ± standard deviation).Temperature/ Glycopyrronium Bromide Glycopyrronium Bromide relative(without acid) (with acid) humidity 1M 2M 3M 6M 1M 2M 3M 6M  5° C. 98.4± 0.9 99.9 ± 1.3 99.3 ± 2.1 99.6 ± 0.4 102.8 ± 1.1 101.4 ± 0.5 103.3 ±0.4 103.5 ± 0.4 25° C./60% 93.8 ± 1.4 91.3 ± 0.7 90.3 ± 1.1 84.2 ± 0.2101.7 ± 0.7 101.9 ± 0.5 102.7 ± 0.0 102.8 ± 0.4 30° C./75% 90.5 ± 4.287.8 ± 1.8 88.9 ± 2.3 — 101.1 ± 1.2 100.7 ± 0.0 102.3 ± 0.4 — 40° C./75%92.5 ± 3.1 88.4 ± 4.7 80.2 ± 1.9 — 100.1 ± 2.4 101.8 ± 0.4 102.0 ± 1.4 —

As shown in Table 2, GLY was relatively unstable when stored undersuboptimal conditions. After 3 months at 40° C./75% RH, the content ofGLY in the samples decreased to about 80%. However, in the presence ofacid there was no significant degradation of GLY at 3 months,irrespective of the storage conditions. The obtained data at 5°; 25°C./60% RH show that in presence of acid the product can be stored bothin normal and accelerated conditions, whereas without acid it is notpossible to store it at 25° C./60% RH.

Example 2 Glycopyrronium Bromide Stability During Storage with DifferentAmount of HCl

Solution formulations were prepared with a composition corresponding tothat of Example 1, Table 1, added with the following different amountsof 1 M HCl.

1M HCl μg/actuation (for a 63 μl valve) μg/μl of the formulation 0.3120.0050 3.13 0.0497 6.25 0.0992 11.8 0.187 15.6 0.248 20.6 0.327 25.00.397 28.1 0.446 46.8 0.743 65.6 1.041

The solutions were filled into conventional aluminium canisters providedwith EPDM valves which were stored inverted for 1 month at 40° C./75%RH. The samples were analyzed chromatographically for glycopyrroniumbromide content, and the values are the mean values from three cans.

No stability issues were found for the whole range of acidconcentrations.

The residual glycopyrronium bromide content ranged from 95.9±0.5% to101.9±2.4% with respect to the content at time 0, and the totaldegradation product ranged from 0.8±0.1% to 3.7±1.0% of the totalcomposition. Moreover when the concentrations of the acid was lower than0.187 μg/μl or higher than 0.743 μg/μl, less residual active ingredient,higher levels of degradation products, and more variability of theirlevels were obtained.

Therefore, stable glycopyrronium bromide HFA solution formulations maybe obtained by using an amount of 1M hydrochloric acid (HCl) in therange of 0.005 to 1.0 μg/μl, preferably of 0.099 to 0.74 μg/μl, and morepreferably 0.18 to 0.32 μg/μl.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A pharmaceutical composition, comprising glycopyrronium bromidedissolved in an HFA propellant and a co-solvent, wherein saidcomposition comprises an amount of hydrochloric acid equivalent to 0.005to 1.0 μg/μl of 1M hydrochloric acid.
 2. A composition according toclaim 1, wherein said composition comprises an amount of hydrochloricacid equivalent to 0.18 to 0.32 μg/μl of 1M hydrochloric acid.
 3. Acomposition according to claim 1, wherein the co-solvent is ethanol. 4.A composition according to claim 1, comprising glycopyrronium bromide inan amount in the range of 0.005 to 0.14% w/w of the composition.
 5. Acomposition according to claim 1, further comprising one or morepharmaceutically active ingredients selected from the group consistingof beta-2-agonists, corticosteroids, antimuscarinic agents, andphosphodiesterase (IV) inhibitors.
 6. A composition according to claim5, comprising formoterol fumarate.
 7. A composition according to claim5, further comprising beclometasone dipropionate.
 8. A metered doseinhaler, comprising a pharmaceutical composition according to claim 1.9. A kit-of-parts, comprising a pharmaceutical composition according toclaim 1 and further comprising one or more pharmaceutically activeingredients for separate, sequential or simultaneous administration,wherein said pharmaceutically active ingredients are selected from thegroup consisting of beta-2-agonists, corticosteroids, antimuscarinicagents, and phosphodiesterase (IV) inhibitors.
 10. A method of fillingan aerosol canister with a pharmaceutical composition according to claim1, comprising: a) preparing a solution comprising glycopyrroniumbromide, a co-solvent, a mineral acid and optionally a low volatilitycomponent; b) filling an open canister with the solution; c) placing avalve onto the canister and crimping; and d) pressure-filling thecanister with HFA propellant through the valve.
 11. A method for theprevention and/or treatment of a respiratory disorder, comprisingadministering an effective amount of a composition according to claim 1to a subject in need thereof.
 12. A method for the prevention and/ortreatment of a respiratory disorder, comprising administering aneffective amount of a composition according to claim 2 to a subject inneed thereof.
 13. A method for the prevention and/or treatment of arespiratory disorder, comprising administering an effective amount of acomposition according to claim 3 to a subject in need thereof.
 14. Amethod for the prevention and/or treatment of a respiratory disorder,comprising administering an effective amount of a composition accordingto claim 4 to a subject in need thereof.
 15. A method for the preventionand/or treatment of a respiratory disorder, comprising administering aneffective amount of a composition according to claim 5 to a subject inneed thereof.
 16. A method for the prevention and/or treatment of arespiratory disorder, comprising administering an effective amount of acomposition according to claim 6 to a subject in need thereof.
 17. Amethod for the prevention and/or treatment of a respiratory disorder,comprising administering an effective amount of a composition accordingto claim 7 to a subject in need thereof.